SUMMARY Seborrheic dermatitis is a chronic relapsing inflammatory skin disorder clinically characterized by scaling and poorly defined erythematous patches. The prevalence of adult seborrheic dermatitis is estimated at 5%. Although the exact cause of seborrheic dermatitis has yet to be understood, Malassezia yeasts, hormones (androgens), sebum levels and immune response are known to play important roles in its development. Additional factors including drugs, winter temperatures and stress may exacerbate seborrheic dermatitis. A variety of treatment modalities are available, including antifungal agents, topical low-potency steroids and calcineurin inhibitors (immunomodulators). This review summarizes current knowledge on the etiopathogenesis and therapy of adult seborrheic dermatitis. KEy WOrds: seborrheic dermatitis, Malassezia yeast, sebum, antifungal agents

INTRODUCTION
Seborrheic dermatitis (SD) is a common chronic relapsing inflammatory skin disorder clinically characterized by poorly defined erythematous patches and scaling. SD primarily affects sebum rich areas, including scalp, face, upper chest and back (1). The prevalence of adult SD is estimated at 5% (2). This condition is more common in males than in females. Among adults, the peak incidence is in the third and fourth decades of life. Although the exact cause of SD has yet to be understood, Malassezia yeasts, hormones (androgens), sebum levels and immune response are known to play important roles in its etiopathogenesis (3). Some researchers propose a pivotal role for Malassezia yeasts (formerly called Pityrosporum ovale) in seborrheic dermatitis (4). Antifungal therapy leads to decreased colonization with Malassezia spp. and concomitant disappearance of skin lesions, which is probably the strongest evidence that Malassezia spp. have momentous role in the development of SD (5). Other therapeutic options include corticosteroids, immunomodulators and antibiotics.

ETIOLOGY AND PATHOGENESIS
Despite quite a high prevalence of this disorder, the exact cause is poorly understood. However, several factors (Malassezia yeasts, hormones, sebum levels, immune response, neurogenic factors, external factors) seem to be involved in SD etiopathogenesis, but the exact pathogenetic mechanism still remains controversial.

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which provides permissive conditions for Malassezia proliferation (17). globosa and M. Keratinocytes at affected areas are stimulated to produce proinflammatory cytokines that further enhance and maintain the inflammatory response. sympodialis. restricta predominate in SD lesions. M. The same study showed increased levels of total serum IgA and IgG antibodies in patients with SD. a more severe clinical presentation of SD (often affecting even extremities) has been observed. have directly shown impaired function of T cells and increased number of NK cells in peripheral blood of SD patients compared to control group (15). Malassezia-driven pathogenetic “vicious circle” closes owing to the fact that saturated fatty acids. but SD is more common in males than in females. Malassezia (M. they can initiate inflammatory response by releasing oleic and arachidonic acid from the sebum lipids (11. They are predominantly situated on lipid-rich anatomic areas. suggesting that increased immunoglobulin production occurs as a response to yeast toxins and lipase activity. largely accompanied by the presence of Malassezia yeast. have an important role in the development of SD. so a certain amount of sebum is always required in order to provide permissive conditions for SD development. it is
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. Both of these unsaturated fatty acids have direct irritative and desquamative effects on keratinocytes. M.
Immune response
Since SD is an inflammatory condition. it could be concluded that in SD patients an abnormal immune reaction to the yeasts occurs.) furfur. are used as a “proliferative fuel” for these yeasts. There is also a possible hormonal link: not only does the disease occur in puberty. during periods of highest sebum production. found infiltration of NK cells and macrophages in SD affected skin areas. sebum rich skin. Interestingly. SD lesions are predominantly located on skin areas rich in sebaceous glands.
Hormones and skin lipids
SD is not always associated with excessive secretion of sebum (13). hence. in HIV positive patients. Since Malassezia spp. Considering the fact that Malassezia may be present on the skin commensally. leading to inflammation and consequent damage of stratum corneum. restricta. Whereas eleven species have been identified. Since bilateral seborrhea occurs in patients with unilateral parkinsonism. there were no elevated titers of antibodies specific to Malassezia antigens. globosa. have the ability to produce lipases. which all together can result in epidermal devastation (16). sebum lipids are essential for Malassezia proliferation and synthesis of initial proinflammatory factors.20(2):98-104
Malassezia species
Growing evidence indicates that Malassezia spp. Furthermore. probably due to the lack of MSH-inhibiting factor as a consequence of insufficient dopaminergic neuronal activity (19).
reasonable to assume that inappropriate immune response may contribute to the pathogenesis.
Neurogenic factors
The frequent occurrence of SD in patients with Parkinson’s disease has long been clinically observed. M. decreases after antifungal therapy with disappearance of skin lesions. particularly in those with prolonged and severe seborrhea. Furthermore. SD is most common in puberty and adolescence. suggesting an influence of androgens on the pilosebaceous unit (14). The number of Malassezia spp. are a major etiologic factor in SD development. are lipophilic yeasts that are ubiquitous residents of the skin (8). However. particularly on the scalp (10). Studies conducted by Bergbrant et al. Faergemann et al. released by Malassezia lipases. obobtusa and M. However. which is influenced by the interplay of other pathogenetic factors that may govern and modulate an individual immune response. despite the presence of hypergammaglobulinemia in SD patients.Bukvić Mokos et al. Therefore. This is probably the strongest evidence that Malassezia spp. As mentioned above. Seborrheic dermatitis
Acta Dermatovenerol Croat 2012. which was also confirmed by several other studies. slooffiae have been detected on affected skin (9). 50% of patients have oily.12). M. with concomitant local activation of complement and proinflammatory cytokine induction. it seems that these changes in sebum level are provo­ked endocrinologically rather than neurologically (18). arachidonic acid metabolized by cyclooxygenase serves as a source of proinflammatory eicosanoids (particularly prostaglandins). M. Malassezia spp. several studies indicate immune dysfunction in SD patients. Although the immunopathogenetic mechanism involved in the development of SD is not clearly understood. This is supported by the findings of increased plasma αmelanocyte stimulating hormone (α-MSH) levels in patients with Parkinson’s disease. seven of them are associated with human skin flora and SD. SD in these patients is considered by some authors as a distinctive entity (“seborrheic-like dermatitis of acquired immunodeficiency syndrome”). The strongest evidence for immunodeficiency as an etiologic factor comes from findings that SD prevalence is significantly higher (34%-83%) among HIV positive and AIDS patients compared to general population (approximately 3%). without provoking any immune reaction or inflammation.

Skin biopsy is rarely needed to verify the diagnosis. uncommonly. presence of concomitant conditions and diseases (especially immuno-compromising). immunologic assessment is required) and in certain photodermatoses. such as scalp. A severe zinc deficiency in patients with acrodermatitis enteropathica and acrodermatitis-like conditions can produce a seborrheic dermatitis-like rash (20).
CLINICAL FEATURES
Typical SD lesions are erythematous patches. with greasy large scales. differential diagnosis also includes atopic and contact dermatitis. which are clinically manifested with chronic eczematous and papulosquamous lesions. but these clinical features of SD may be confused with psoriasis.20(2):98-104
Namely. responsible for the frequent occurrence of SD in patients treated with neuroleptic drugs. rosacea. Common SD does not respond to supplementary zinc therapy. nasolabial folds. which develop to patches that resemble the shape of flower petals or medallion. thus additionally contributing to the tendency of SD development. at least partially. today’s therapeutic approach is commonly based on topical antifungal. Traditionally. more serious dermatologic disorders. Another common symptom
MANAGEMENT AND THERAPY
Since the key underlying pathogenetic mechanisms of SD include excessive Mallasezia spp. To facilitate distinction. relapse of the disease is more common in low fall and winter. patients presenting with skin lesions suspect of SD should be thoroughly considered for the possible presence of other. whereas in other seborrheic conditions such as acne. Seborrheic dermatitis
Acta Dermatovenerol Croat 2012. especially on the scalp and in the ear canal. This sebostatic effect of L-dopa is limited exclusively to patients with Parkinson’s disease. diet is blamed for the development of SD. Furthermore. the diagnosis is not simple. Given that desquamation is regularly present. The disorder has a predilection for areas with numerous sebaceous glands. In some patients. and. In some individuals. L-dopa has no effect on sebum production (19). When only this manifestation is present. A patient with erythematous and scaling plaques in the areas such as scalp. Furthermore. A serious variant of this skin disorder is generalized exfoliative erythroderma (seborrheic erythroderma). back. nail pitting and distal onycholysis may be helpful. nasolabial folds. dermatophytosis. glabella. umbilicus and groins. Two forms of SD may occur on the chest. cutaneous lymphoma or Langerhans cell histiocytosis. The occurrence of so-called seborrhiasis could be found. The pityriasiform type is probably an acute severe form of petaloid SD (7). a high rate of seborrhea is reported among combat troops in war times (20). but this could be attributed to the tendency of depressed patients to remain indoors.
Other factors
SD has a seasonal aspect. Frequent occurrence of SD is also observed in depressive disorders. leading to misdiagnosis. The petaloid type starts with red to brown follicular and perifollicular papules. SD changes on the trunk sometimes may be misinterpreted as tinea versicolor that can easily be distinguished with Wood light examination and presence of hyphae on scraped KOH cytologic preparation. hairline. ears. as well as in patients with tardive dyskinesia. indicating a condition with overlapping psoriasis and SD on the face. upper chest.Bukvić Mokos et al. findings of sharply demarcated scalp plaques.
DIFFERENTIAL DIAGNOSIS
Although in everyday practice SD can usually be diagnosed at the first sight. significant improvement can also be achieved by antibiotics (met-
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. and associated histologic changes may vary from acanthosis and parakeratosis to spongiosis. eyebrows and retroauricular regions has most likely SD. as well as to altered hygiene habits. This type has generalized maculae and patches that follow the skin lines mimicking pityriasis rosea. central nervous system trauma and facial nerve palsy. facial immobility of Parkinson’s disease patients (mask-like face) can secondarily lead to the increased sebum accumulation. Scalp lesions may extend into the forehead skin and form scaly erythematous border called “corona seborrheica“. gender. keratolytics are also highly effective. a common petaloid type and quite rare pityriasiform type (6). treatment with L-dopa successfully restores MSH-inhibiting factor synthesis and reduces sebum secretion in parkinsonian patients. Patients often report pruritus. candidiasis. The condition can be triggered by emotional stress. affected sites.
of SD is blepharitis with honey-colored crusts along the rim of the eyelid. proliferation with consequent induction of local skin inflammatory response. The patient’s age. eyebrow. antiinflammatory and immunomodulatory agents. as they are typically present in psoriatic patients (21). family history as well as everyday habits must be taken in consideration on differential diagnosis. chronic dermatitis of the ear canal may be the only manifestation of SD. axillae. Facial SD lesions may resemble skin changes found in systemic lupus erythematosus (if suspected. Similar mechanisms may be.

used once daily. also effectively maintains remission (23). intermittently used. Azole class of antifungal agents (lanosterol 14 α-demethylase inhibitors) proved to be most effective in growth inhibition of Malassezia spp. only in severe cases with strikingly outspread lesions. such as tea tree oil and 90% honey diluted in warm water. rare cases of malignancy (e. such as shampoos.. Intermittent use of ketoconazole 2% shampoo (once weekly) has been shown to have a significant prophylactic effect (22). (32). Systemic therapy is rarely required. vehicle-controlled 4-week efficacy trial of twice daily pimecrolimus 1% cream in 96 patients.25).20(2):98-104
ronidazole). In two randomized clinical trials.
Zinc pyrithione
Zinc pyrithione is a common active ingredient in most of the over-the-counter anti-dandruff shampoos and has both antifungal and antimicrobial effects (39). as shown and validated by multiple randomized clinical trials.Bukvić Mokos et al. skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors. Bifonazole 1% cream.g. Ketoconazole 2% cream significantly improves SD lesions of the face and chest used twice daily (effective as hydrocortisone 1% cream) and.5% shampoo with salicylic acid 3% or zinc pyrithione 1% are also effective
Metronidazole
There are contradictory data on the effectiveness of topical metronidazole 0. double blind. creams and gels. telangiectasias. Some alternative therapeutic approaches have also been reported. These agents are not associated with the side effect profile of corticosteroids. ketoconazole applied in various vehicles showed superior effects.03% and 0. used twice weekly. today it is generally accepted that initial therapy for SD should be based on topical antimycotics. Often and prolonged use is not recommended because of their well-known side effects such as atrophy. and hence it is the first-line treatment for SD. However.
Antifungal medications
Although earlier treatment approaches were focused on antiinflammatory agents. tar and phototherapy. is usually effective in the treatment of SD of the scalp and face (24. Seborrheic dermatitis
Acta Dermatovenerol Croat 2012.05% in reducing symptoms and lowering the number of Malassezia spp.
TOPICAL THERAPY
Topical agents are effective and well tolerated in the majority of SD cases. A combination ointment containing 1% bifonazole and 40% urea helps reduce the symptoms of scalp SD (26). hypertrichosis and perioral dermatitis. Koca et al. associated with the development of SD. topical calcineurin inhibitor therapy was effective and well tolerated in the treatment of SD (37). pimecrolimus 1% cream and tacrolimus 0. but today also empirically well-known from everyday clinical practice.75% gel.1% ointment decrease cutaneous inflammation by inhibiting Tlymphocyte driven cytokine production (36). In two trials. metronidazole showed better efficacy than placebo and was as effective as ketoconazole 2% cream (33. Antifungal agents are still the first choice in the treatment of SD due to the fact that ketoconazole 2% has been shown to be superior to betamethasone diproprionate 0.34). There is a consensus that topical corticosteroids are useful in short term mainly to control erythema and itching. Miconazole is an azole that can also be effectively used in the treatment of SD as a monotherapy or in combination with hydrocortisone (27). Ketoconazole is available in different topical overthe-counter preparations.
(29). Ketoconazole shampoo 2% is effective in treating scalp SD. pimecrolimus 1% proved to be as effective as topical corticosteroids (hydrocortisone acetate 1% cream or betamethasone 17-valerate 0. as well as in cases unresponsive to topical treatment. found metronidazole not superior to placebo in patients with SD (35). Topical corticosteroids can be used alone or in combination with antifungal agents. low to mild potency topical corticosteroids are effective in fast clearing of visible signs and associated symptoms (31). ciclopirox 1% cream.
Calcineurin inhibitors
Topical calcineurin inhibitors. Another topical antifungal agent. This agent is available in concentrations of
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. Among the azoles. Conversely. Combinations of ciclopirox 1.. In a randomized. Recent studies show statistical non-inferiority of ciclopirox in comparison with ketoconazole (30).
Corticosteroids
In severe cases of SD. Ciclopirox has both antifungal and antiinflammatory properties (28). long-term use is not recommended and application should be limited to lesions of SD (38). Ketoconazole also has slight antiinflammatory properties. and it is principally well tolerated in all available formulations.1% cream) (1). Due to this fact. is likewise effective and provides a reduction of symptoms when used twice daily.

but long-term use should be avoided because of their well-known side effects.111:14-7. In another double blind study involving 63 patients. On deciding on oral antimycotic therapy. Batra R. particularly in severe. Beiber T. was shown to be more effective than placebo in an 8-week trial involving 129 patients with facial lesions (43). Lithium gluconate 8% ointment. Am Fam Physician 1995. which must be strictly distinguished from seborrhea. 7. but among the many identified etiopathogenetic factors. relapsing. Summerbell RC. In a randomized. In: Bologna JL. Also. 174 patients with SD received either 250 mg of terbinafine or placebo
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. The median number of treatment sessions was 23 and the median cumulative UVB dose was 9. Plewig G. therapy-resistant form. The etiology is still not completely understood. 159-60. 2008. New York: Mosby. double blind.21:401-12. 2003.
for 6 weeks. Evidence-Based Dermatology. 18 patients with severe SD were treated with narrow-band UVB three times per week until the clearance or upon completing 2 months of therapy (45). selenium sulfide 2. and therefore today are considered as the firstchoice treatment for SD. All patients showed improvement. Wolff HH. can be a predictor of some serious conditions such as HIV infection. Shwartz RA. Seborrheic dermatitis
Acta Dermatovenerol Croat 2012.
Selenium sulfide
In a randomized double-blind trial involving 246 patients with moderate to severe dandruff. Although SD per se does not seriously disrupt the patient’s quality of life. Gupta AK. 2. editors. Seborrheic dermatitis. ketoconazole (200 mg daily dose for 4 weeks) showed significant improvement (48). The biggest drawback of UVB irradiation is rapid disease relapse appearing 2-6 weeks after treatment. Jorizzo JL. but it might still be effective to clear visible signs of the disease when used alone or in combination with ketoconazole (41). In a randomized trial involving 12 patients. Landhalter M. In: Burgdorf WHC. Other types of dermatitis. Del Rosso JQ. Oral terbinafine was not more effective than placebo in patients with facial SD.
References
1. Zinc pyrithione has shown inferior efficacy than ketoconazole in several trials.15:1-4. Therapeutic update on sebborheic dermatitis.
Phototherapy
Many patients notice improvement during the summer. 3. placebo-controlled study. Stefanaki I. Local glucocorticoids are also effective. editors. Fritsch PO. Both medicated shampoos showed greater efficacy than placebo. In an open prospective study. pp. Cooper EA.5% was tested against ketoconazole 2% and placebo. Skin Ther Lett 2010. Katsambas A. 6. Picardo M. Seborrheic dermatitis. oral fluconazole in a 300 mg single weekly dose showed no significant therapeutic effect (47).
SYSTEMIC THERAPY: ORAL ANTIFUNGAL MEDICATIONS
Data on the effectiveness of systemic antifungal therapy are not consistent. it should be kept in mind that its occurrence. satisfactory therapeutic results are achieved by topical antifungal agents of the azole class that are principally well tolerated without significant side effects. lithium succinate 8% ointment showed greater efficacy than placebo in the treatment of visible signs of the disease in HIV-positive patients (42). Camelli N. In the majority of cases. 5. Blackwell Publishing.
CONCLUSION
Seborrheic dermatitis is a chronic. 4. but in other areas terbinafine showed greater efficacy than placebo (46). Other eczematous eruptions. editor.8 J/cm2. Rapini RP. Kim GK. 215-8. used twice daily. probably due to their antiinflammatory effects. Dermatology. but burning and itching may occur during phototherapy. there are risks associated with exceeding the maximum lifetime allowable cumulative dose and carcinogenic effects on the skin. lithium gluconate 8% ointment is more effective than ketoconazole 2%.Bukvić Mokos et al. Janniger CK. 164-70. Dermatol Clin 2003.52:149-55.20(2):98-104
1% and 2% in shampoos as well as a 1% cream formulation (40). Malassezia yeast has certainly a pivotal role. the cost-benefit ratio must be carefully considered due to the possible hepatotoxic effect of systemic antifungals. pp. papulosquamous inflammatory skin disorder. Also. especially those with severe disease. Bluhm R. but ketoconazole was better tolerated (44). Reider N.
Lithium salts
Topical lithium succinate and lithium gluconate are effective agents in treating SD in the areas other than scalp. Seborrheic dermatitis and Malassezia species: how are they related? J Clin Aesth Dermatol 2009. Seborrheic dermatitis. Phototherapy using UVB rays is sometimes considered as an option for severe or recalcitrant SD. In: Williams H. In one trial involving 19 patients.